Renal Single Cell Genomics Links Type II Interferon and Lupus Nephritis in African-Americans

Andrea Fava¹, Yuji Zhang ², Jill Buyon ³, Chaim Putterman ⁴, Nir Hacohen ⁵, Arnon Arazi ⁵, Celine Berthier ⁶, Deepak Rao ⁷, Michael Brenner ⁸, David Wofsy ⁹, Anne Davidson ¹⁰, Mathias Kretzler ¹¹, David Hildeman ¹², E. Steve Woodle ¹², Betty Diamond ¹⁰, Thomas Tuschl ¹³, Evan Der ¹⁴, Hemant Suryawanshi ¹³, H. Michael Belmont ¹⁵, Peter Izmirly ¹⁶, Robert Clancy ¹⁶, The Accelerating Medicines Partnership ¹⁷ and Michelle Petri ¹⁸, ¹Johns Hopkins University, Baltimore, ²University of Maryland, Baltimore, ³NYU School of Medicine, New York, ⁴Albert Einstein College of Medicine, New York, NY, ⁵Broad Institute, Cambridge, ⁶University of Michigan, Ann Arbor, MI, ⁷Brigham and Women's Hospital, Boston, MA, ⁸Brigham and Women’s Hospital:, Boston, ⁹UCSF, San Francisco, ¹⁰Feinstein Institutes for Medical Research, Manhasset, ¹¹University of Michigan, Ann Arbor, ¹²University of Cincinnati, Cincinnati, ¹³Rockefeller Research Laboratories, New York, ¹⁴Albert Einstein College of Medicine, New York, ¹⁵New York University School of Medicine, Ney York, ¹⁶New York University School of Medicine, New York, ¹⁷Multiple Organizations, USA, ¹⁸Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: genomics, Lupus nephritis, race/ethnicity and interferons, Systemic lupus erythematosus (SLE)

Session Information

Date: Monday, November 11, 2019

Title: SLE – Etiology & Pathogenesis Poster I

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Compared to Caucasian, African-American ethnicity is associated with a higher risk of developing systemic lupus erythematosus, lupus nephritis, high-risk histological features, resistance to treatment, and mortality. In phase 1 of the Accelerating Medicines Partnership (AMP), we used single-cell genomics to identify ethnicity associated features.

Methods: Single cell RNA sequencing was performed on renal biopsies obtained for clinical purpose; one pipeline applying CEL-Seq2 in a leukocyte enriched sample and the other Fluidigm C1 800 in an agnostic approach to dissociated renal cells. Differential abundance of cell populations was determined using a logistic mixed model. Then, the differential expression profile was determined for each cell cluster and interpreted using pathway enrichment analysis.

Results: Samples from 19 African-American and 20 Caucasian patients were obtained. We identified 30 cell clusters. Type I and II interferon inducible genes were upregulated in most cell populations. A cluster of T cells with exceptionally high interferon signature was found to be increased in African-Americans (OR 4.8). Macrophages and DC4-like dendritic cells were instead less abundant (OR 0.3). In African-Americans, type I and II interferon response pathways were enriched in several cell types including T cells, B cells, plasma cells, and activated monocytes. The majority of the differentially expressed genes was specifically inducible by type II interferon. In addition, while there was no local expression of type I interferons, interferon gamma was abundantly expressed by infiltrating NK and CD8 T cells.

Conclusion: African-American patients with lupus nephritis have a stronger interferon response pathway activation, especially type II. Our findings suggest an intrinsic biological factor underlying the outcome gap and highlight the role of interferon gamma in lupus nephritis, implicating this pathway as a potential therapeutic target in SLE. Further work in Phase 2 of AMP is being pursued to validate and extend these findings.

Disclosure: A. Fava, None; Y. Zhang, None; J. Buyon, Bristol Myers Squibb, 5, Exagen Diagnostics, 2; C. Putterman, Equillium, 5, Equillium, Inc, 2, 5, Exagen, 2; N. Hacohen, Neon Therapeutics, 1, 8; A. Arazi, None; C. Berthier, None; D. Rao, Janssen, 5, Merck, 2, Pfizer, 5; M. Brenner, None; D. Wofsy, Celgene, 5, Genentech, 5, GlaxoSmithKline, Lilly, 5, Novartis, Principia, 5; A. Davidson, None; M. Kretzler, None; D. Hildeman, None; E. Woodle, None; B. Diamond, GSK, 5, Jansen, 5, Lilly, 5; T. Tuschl, None; E. Der, None; H. Suryawanshi, None; H. Belmont, None; P. Izmirly, Glaxosmithkline, 5, GSK, 5; R. Clancy, None; T. Accelerating Medicines Partnership, None; M. Petri, Eli Lilly and Company, 5, Exagen, 2, 5.

To cite this abstract in AMA style:

Fava A, Zhang Y, Buyon J, Putterman C, Hacohen N, Arazi A, Berthier C, Rao D, Brenner M, Wofsy D, Davidson A, Kretzler M, Hildeman D, Woodle E, Diamond B, Tuschl T, Der E, Suryawanshi H, Belmont H, Izmirly P, Clancy R, Accelerating Medicines Partnership T, Petri M. Renal Single Cell Genomics Links Type II Interferon and Lupus Nephritis in African-Americans [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/renal-single-cell-genomics-links-type-ii-interferon-and-lupus-nephritis-in-african-americans/. Accessed .

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